Polygenic regulation of PTSD severity and outcomes among World Trade Center responders

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition triggered by exposure to trauma. The study of PTSD is complicated by highly heterogeneous presentations and experiences of trauma between individuals. Capitalizing on the existence of the World Trade Center General Responder Cohort (WTC-GRC) of rescue, recovery and clean-up workers who responded during and in the aftermath of the World Trade Center (WTC) 9/11/2001 attacks, we studied genetic correlates of PTSD in a sample of 371 WTC responders, selected from the WTC-GRC utilizing stratified random sampling. This deeply phenotyped sample of WTC responders – ranging from no/low PTSD symptom levels to severe PTSD– provide a unique opportunity to study genetic risk factors for PTSD severity and chronicity following a single, shared, well-documented trauma, also incorporating measures of childhood and other lifetime traumas. We examined associations of polygenic risk scores (PRS) –derived from a range of genome-wide association studies (GWAS) of behavioral traits, psychiatric disorders, and brain volumetric phenotypes– with PTSD severity and chronicity among these 371 individuals. Our results demonstrate significant genetic regulation of lifetime PTSD severity, assessed with the lifetime version Clinician-Administered PTSD Scale (CAPS), and chronicity, assessed with the past-month CAPS. PRS derived from GWAS of attention deficit-hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and brain imaging phenotypes (amygdala and putamen volumes) were associated with several PTSD symptom dimensions. Interestingly, we found greater genetic contribution to PTSD among cases compared to our full sample. In addition, we tested for associations between exposures to traumatic stressors, including WTC-related exposures, childhood trauma, and other lifetime traumatic life events in our full sample. Together, polygenic risk and exposures to traumatic stress explained ~45% of variance in lifetime CAPS (R2=0.454), and ~48% of variance in past-month CAPS (R2=0.480) in the full sample. These participants represent a highly vulnerable population, with exposures to severe trauma during 9/11 and the following days and months. These novel identified associations between PTSD and PRS of behavioral traits and brain volume phenotypes, as well as replicated associations with PRS of other psychiatric disorders, may contribute to understanding the biological factors associated with risk for and chronicity of PTSD. In particular, the identification of neuroimaging phenotypes indicates that coupling of neuroimaging with genetic risk score calculations may predict PTSD outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by NIOSH: Biomarkers of Psychological Risk and Resilience in WTC Responders U01 OH010407 PIs: A Feder, RH Pietrzak, SM Southwick ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study, conducted between April 2013 and September 2017, was approved by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai, and all participants provided written informed consent. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary data will be made available upon publication.